Selegiline (deprenyl) is a selective inhibitor of cerebral monoamine oxidase type B at the dosage (10 mg/day) used in patients with Parkinson's disease. Through this activity, the drug increases nigrostriatal dopamine levels, and may protect neurons against damage by free radicals and possibly exogenous neurotoxins. Selegiline also inhibits dopamine reuptake from the synaptic cleft. Because of its selectivity, selegiline 10mg daily does not prevent the breakdown and exacerbate the indirect pressor effects of dietary amines such as tyramine; it is devoid of the 'cheese' effect. Following oral administration, selegiline is rapidly metabolised to L-methamphetamine and L-amphetamine, which may account for the euphoria and insomnia seen in many patients, although potentiation of dopaminergic activity with concurrent levodopa appears more likely. The drug is a useful adjunct to levodopa in Parkinsonism, improving 'end-of-dose' fluctuations, producing modest improvements in motor function, and allowing a reduction in levodopa dosage. Indeed, if levodopa dosages are not decreased when selegiline is added to the therapeutic regimen, peak concentration dyskinesias due to levodopa are often exacerbated. However, symptomatic benefits are rarely maintained for more than a year and selegiline is relatively ineffective in allaying the abrupt swings in response to levodopa ('on/off' effects). When used alone in patients with mild disease, selegiline appears to slow the rate of symptom progression and may extend survival, through either neuroprotection or symptom relief. Whichever mechanism(s) is responsible, there is strong evidence to suggest that selegiline should be considered both in patients newly diagnosed with Parkinson's disease in an attempt to delay symptom progression, and in those experiencing dose-dependent fluctuations in response to levodopa.

The effects of histamine have been studied on separated circular and longitudinal myometrial layers from the guinea-pig. Virgin guinea-pigs in dioestrus were (1) untreated, (2) treated for 14 days thrice weekly with oestradiol cypionate 20 micrograms/kg s.c., or (3) treated as in (2) but in addition with progesterone 3 mg/animal s.c. daily for 4 days before use. Preparations were field-stimulated (60 V 2 ms 30 Hz for 5 s every 100 s) to elicit regular contractions. Histamine was equipotent in producing enhancement of evoked contractions of circular myometrium from animals in each treatment group (pD2 = 5.03, 5.05 and 4.95 in groups 1, 2 & 3 respectively), and enhanced contractility in all but two longitudinal myometrial preparations. Treatment with oestradiol alone, and with oestradiol and progesterone following oestradiol priming enhanced the magnitude of maximal response and produced a small decrease in the potency of histamine on the longitudinal myometrium. pA2 estimates for mepyramine as an antagonist were similar (8.6) in preparations of longitudinal myometrium from each group of animals. Metiamide (1-10 mumol/l) did not antagonise the effects of histamine in this layer. These results, taken together, indicate that ovarian steroids act selectively on the longitudinal myometrial layer to amplify the action of histamine, but do not alter the histamine receptor subtype which in this layer is exclusively H1.

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Urapidil is a postsynaptic alpha 1-adrenoceptor antagonist with a pharmacodynamic profile similar to prazosin. Unlike prazosin, however, urapidil also has some central activity which may explain the apparent improved tolerability of urapidil, including the absence of first-dose syncope. In clinical trials urapidil therapy resulted in significant reductions in blood pressure in patients with mild to severe essential hypertension, with little influence on heart rate. It is an effective antihypertensive when administered as monotherapy or in combination with beta-blockers and thiazide diuretics. In the few patients with cardiac dysfunction who have been studied to date, urapidil has improved myocardial oxygen consumption, systemic vascular resistance, left ventricular function, cardiac output and pulmonary capillary wedge pressure; however, further study is needed to assess the full therapeutic potential of urapidil in these patients. Urapidil has also been used successfully in the treatment of hypertensive emergencies, including eclampsia and pre-eclampsia, hypertensive crisis and hypertension occurring during general and cardiac surgery, rapidly lowering blood pressure without altering heart rate. Urapidil does not affect lipid or glucose metabolism, nor does it impair renal function. In addition, urapidil may be beneficial to patients with pulmonary hypertension, in whom it dilates pulmonary vascular beds to a greater extent than systemic vasculature, although therapeutic trials have not examined this effect. The most common adverse effects associated with urapidil therapy are dizziness, nausea, headache, fatigue and palpitations; however, these tend to be mild and transient and usually do not require discontinuation of treatment. Thus, urapidil offers a useful alternative to currently available drugs for the treatment of mild to severe hypertension, either as monotherapy or in combination with other antihypertensive drugs.

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